Overexpression of thioredoxin in Fanconi anemia fibroblasts prevents the cytotoxic and DNA damaging effect of mitomycin C and diepoxybutane.
Adult T cell leukemia derived factor (ADF)/thioredoxin (Trx) is known to be an important intracellular antioxidant involved in a number of redox reactions such as ribonucleotide reductase (RNR) as well as of tyrosinase. Since RNR is a key enzyme of nucleotide metabolism and DNA synthesis, a reduced Trx level would result in reduced enzymatic activity and cause DNA damage. Furthermore, Trx is considered to be an effective regulator of redox sensitive gene expression. The role of Trx in nucleotide metabolism and gene expression may be an explanation for increased chromosomal instability as well as hypersensitivity towards oxygen, ROI and ROI generating agents. The activity of tyrosinase, the key enzyme of melanin biosynthesis, is influenced by the thioredoxin level and by superoxide radicals. Low thioredoxin levels and high superoxide concentrations activate tyrosinase causing hyperpigmentation of the skin. In addition to the observed high superoxide concentration in Fanconi anemia (FA) patients, a low thioredoxin level might be responsible for the hyperpigmentation (café-au-lait spots) in this disease. We observed that overexpression of the thioredoxin cDNA in FA fibroblasts completely abolished the DNA damaging effects of mitomycin C and diepoxybutane and inhibited the constitutive activity of the nuclear factor kappaB (NF-kappaB) in SV40 transformed FA fibroblasts. However, spontaneous chromosomal breakage was not affected.
Ruppitsch
W
W
Institut für Biochemie, Freie Universität Berlin, Berlin-Dahlem, Germany. wrupp@chemie.fu-berlin.de
Meisslitzer
C
C
Hirsch-Kauffmann
M
M
Schweiger
M
M
D000975:Antioxidants / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D019457:Chromosome Breakage / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004852:Epoxy Compounds / Q000037:antagonists & inhibitors / Q000633:toxicity*; D005199:Fanconi Anemia / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D008297:Male; D015162:Micronucleus Tests; D016685:Mitomycin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D013879:Thioredoxins / Q000378:metabolism*; D014162:Transfection / Q000235:genetics; D014170:Transformation, Genetic / Q000235:genetics
D000975:Antioxidants; D016207:Cytokines; D004852:Epoxy Compounds; D016328:NF-kappa B; D009363:Neoplasm Proteins; C055533:adult T cell leukemia-derived factor; D016685:Mitomycin; D013879:Thioredoxins; C007366:diepoxybutane